Abstract
Unconditioned hematopoietic stem cell transplantation (HSCT) is the recommended treatment for patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency with an HLA-matched sibling donor (MSD) or family donor (MFD). Improved overall survival (OS) has been reported compared to the use of unrelated donors, and previous studies have demonstrated that adequate cellular and humoral immune recovery can be achieved even in the absence of conditioning. Detailed insight of the long-term outcome is still limited. We aim to address this by studying a large single-center cohort of 28 adenosine deaminase-deficient patients who underwent a total of 31 HSCT procedures, of which more than half were unconditioned. We report an OS of 85.7% and event-free survival of 71% for the entire cohort, with no statistically significant differences after procedures using related or unrelated HLA-matched donors. We find that donor engraftment in the myeloid compartment is significantly diminished in unconditioned procedures, which typically use a MSD or MFD. This is associated with poor metabolic correction and more frequent failure to discontinue immunoglobulin replacement therapy. Approximately one in four patients receiving an unconditioned procedure required a second procedure, whereas the use of reduced intensity conditioning (RIC) prior to allogeneic transplantation improves the long-term outcome by achieving better myeloid engraftment, humoral immune recovery, and metabolic correction. Further longitudinal studies are needed to optimize future management and guidelines, but our findings support a potential role for the routine use of RIC in most ADA-deficient patients receiving an HLA-identical hematopoietic stem cell transplant, even when a MSD or MFD is available.
Highlights
Adenosine deaminase (ADA) deficiency results in one of the more common forms of autosomal recessive severe combined immunodeficiency (SCID) [1, 2]
The youngest patient was under a month old when transplanted, and the oldest patient, who had previously been treated by gene therapy (GT), was 119.6 months old
The initial stem cell infusion for one of the patients was of cord blood (CB) origin
Summary
Adenosine deaminase (ADA) deficiency results in one of the more common forms of autosomal recessive severe combined immunodeficiency (SCID) [1, 2]. ADA expression is high in lymphoid tissues, and ADA deficiency leads to severe abnormalities in lymphoid development [4,5,6] It is typically associated with lymphopenia with abnormal T, B, and natural killer (NK) cell numbers and function. Patients display typical non-immunological features, including sensorineural hearing loss [7, 8], non-infectious pneumonitis, and pulmonary alveolar proteinosis [9, 10], skeletal dysplasias [11,12,13,14], urogenital abnormalities [15], hepatic dysfunction [16], cognitive impairment, and behavioral abnormalities [17, 18] This variety of clinical manifestations can be explained by the metabolic pathogenesis affecting multiple organs and tissues [3]. The survival associated with GT, which is currently 100%, invites comparison with HSCT outcomes
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